HGG Advances最新文献

{"title":"CRISPR-engineered deletion of POGZ alters transcription factor binding at promoters of genes involved in synaptic signaling.","authors":"Mariana Moyses-Oliveira, Yating Liu, Serkan Erdin, Dadi Gao, Riya Bhavsar, Kiana Mohajeri, Kathryn O'Keefe, Philip M Boone, Gabriela Xavier, Calwing Liao, Aiqun Li, Rachita Yadav, Monica Salani, Diane Lucente, Benjamin Currall, Celine E F de Esch, Derek J C Tai, Douglas Ruderfer, Kristen J Brennand, James F Gusella, Michael E Talkowski","doi":"10.1016/j.xhgg.2026.100652","DOIUrl":"10.1016/j.xhgg.2026.100652","url":null,"abstract":"<p><p>One of the seminal discoveries from genetic studies of autism spectrum disorder and related neurodevelopmental disorders (NDDs) has been that loss-of-function (LoF) mutations in genes that impact transcriptional regulation confer substantial liability to NDDs. Haploinsufficiency of the epigenetic regulator POGZ represents one of the strongest such associations; however, little is known about the mechanisms by which POGZ LoF alters early neuronal development. Here, we created an allelic series of CRISPR-engineered human induced pluripotent stem cell (hiPSC) clones harboring mono- and bi-allelic POGZ deletions. In hiPSC-derived neural stem cells (NSCs) and Neurogenin-2-induced neurons (iNs), POGZ LoF altered the expression of genes associated with synaptic and intracellular signaling and extracellular matrix organization. Our multiomics profiling also showed altered footprinting of critical transcription factors (e.g., activator protein 1 complexes) that were enriched at promoters of differentially expressed genes associated with synaptic function. To further interrogate the shared molecular changes associated with NDDs, we compared our results to deletions of the transcription factor MEF2C and the sodium channel gene SCN2A that we generated in these same isogenic iNs. These analyses revealed strong enrichment of extracellular matrix and intracellular signaling disruption associated with POGZ and MEF2C deletion, whereas POGZ and SCN2A haploinsufficiency exhibited shared transcriptional effects on gene modules enriched for NDD-associated genes with opposing regulatory effects. Notably, we also observed alterations to synaptic firing rate and neurite extension with bi-allelic deletions. These shared molecular consequences suggest key points of convergence that connect gene regulation to neuronal function in the etiology of neurodevelopmental pathologies.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100652"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13429924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148425031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALG14 variants contribute to a congenital disorder of glycosylation characterized by congenital myasthenia and epilepsy.","authors":"Jonathan Marquez, Flavien Rouxel, Fatima E It, Victor Couturier, Laurence Duplomb, Valentin Bourgeois, Anne-Sophie Briffaut, Ange-Line Bruel, Martin Chevarin, Benjamin Ganne, Bobby G Ng, Stephen Viviano, Mara P N Hektor, Rafia A Pasha, Vincent Gatinois, Camille Larrieu-Arguille, Jean-Michel Faure, Olivier Prodhomme, Maxime Colmard, François Rivier, Okubo Yukimune, Charlotte Poe, Isabelle Rouvet, Antonio Vitobello, Christel Thauvin, Gerardo D Rodriguez-Gomez, Leandra K Tolusso, Yu Katata, Atsuo Kikuchi, Trevor L Hoffman, Hans C Andersson, Engin Deniz, Miao He, Constance F Wells, Anne-Sophie Denommé-Pichon, Andrew C Edmondson, Hudson H Freeze, Christina Lam","doi":"10.1016/j.xhgg.2026.100650","DOIUrl":"10.1016/j.xhgg.2026.100650","url":null,"abstract":"<p><p>Asparagine-linked glycosylation 14 (ALG14) is a UDP-GlcNAc transferase that catalyzes the second sugar addition in the synthesis of the dolichol-linked oligosaccharide precursor in N-linked glycosylation, ultimately contributing to the glycosylation of a wide array of proteins. Bi-allelic pathogenic variants in ALG14 have been suggested to lead to a congenital disorder of glycosylation (CDG) due to incomplete lipid-linked oligosaccharide synthesis and ultimately hypoglycosylation of N-linked glycoproteins. In a cohort of nine previously unreported individuals with bi-allelic variants in ALG14 from eight unrelated families, we demonstrate evidence of a CDG that manifests as a congenital myasthenic syndrome, epilepsy, joint contractures, and dysmorphic features. Using a Xenopus knockdown model of disease, we explored the ramifications of alg14 depletion on early neurodevelopment and used this model as a platform to test the function of previously identified ALG14 missense variants, as well as missense variants from the individuals reported in this study. Investigations of Xenopus model tissue and tissue from an affected individual elucidated a mechanism by which dysfunctional glycosylation may lead to neurological disease and establish this as a bona fide CDG. In the future, these findings may guide the evaluation of individuals with suspected ALG14-CDG and targeted therapeutics such as those being used in other CDGs.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100650"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pleiotropic landscape of rare variant associations with multiple cancers in large biobanks.","authors":"Austin Hammermeister Suger, Tabitha A Harrison, Jiachen Zhang, Michael C Wu, Burcu F Darst, Sara Lindström","doi":"10.1016/j.xhgg.2026.100662","DOIUrl":"10.1016/j.xhgg.2026.100662","url":null,"abstract":"<p><p>Previous association studies between germline rare genetic variation and cancer risk have primarily examined a limited number of cancers in clinical samples, often with participants predominantly of European genetic ancestry. We conducted exome-wide rare variant association analyses across 70+ cancer types using data from more than 729,000 participants from the UK Biobank (UKB) and All of Us (AoU) Research Program cohorts. We used generalized linear mixed models to screen for cancer pleiotropic effects by conducting gene-based and single-variant tests of predicted loss of function (pLoF) and missense variants and six groups of cancer defined by biological and etiological similarities. We then assessed significant genes for associations with 27 individual cancer types that had data for at least 500 affected individuals. Of the 33 potential pleiotropic genes identified, 16 consistently showed significant associations across ≥3 individual cancer types. For example, the presence of at least one CHEK2 pLoF variant was associated with increased odds of diagnosis with 14 different cancers (odds ratio [OR] range: 1.34-3.21). Similarly, the presence of at least one RTEL1 missense variant was associated with lower odds of diagnosis with 9 cancers (OR range: 0.67-0.88). Our results expand our knowledge about these loci and point to a larger impact on overall cancer risk than previously appreciated.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100662"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13571141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aggregate variant calling using short reads enables population and disease studies for paralogous genes.","authors":"Timofey Prodanov, Sang Yoon Byun, Vikas Bansal","doi":"10.1016/j.xhgg.2026.100653","DOIUrl":"10.1016/j.xhgg.2026.100653","url":null,"abstract":"<p><p>Variant calling in paralogous genes using short-read sequencing is problematic due to mapping ambiguity between highly similar sequences. Aggregate variant calling, which treats paralogous loci as a single locus by realigning reads to a masked reference genome, can enable variant detection in paralogous genes. We used our informatics tool Parascopy to assess the accuracy of aggregate variant calling in paralogous genes using short-read data. Parascopy achieved significantly higher recall compared to standard variant calling without sacrificing precision. We identified 158 paralogous genes with over 25 percentage points improvement in recall using simulated data and 118 genes with at least 10 percentage points improvement in recall across Genome in a Bottle (GIAB) reference samples. Across 1000 Genomes samples, aggregate genotypes in paralogous genes were highly concordant between whole-genome and whole-exome data (r² = 0.9998). Using sequence data from population and disease cohorts, we utilized aggregate variant calls to perform population-genetic analysis, case-control association analysis, and haplotype phasing in specific disease-relevant paralogous genes that are inaccessible to standard diploid variant calling. Specifically, in the SMN1 gene, we identified tag-SNPs for two-copy SMN1 haplotypes and showed that specific low-frequency missense variants in African populations occurred exclusively on such haplotypes. For the CFC1 gene-previously implicated in heterotaxy syndrome-association analysis using exome data indicated that loss-of-function variants are unlikely to be associated with heterotaxy in individuals with congenital heart disease. Finally, we utilized aggregate genotypes to perform haplotype phasing for the X-linked gene IKBKG, achieving 99.2% concordance between trio-based and statistical phasing approaches.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100653"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13475201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148537227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-ancestry genome-wide association meta-analysis of hepatocellular carcinoma identifies 15 risk loci including MAP3K9, DHRS1, MTTP, and 8q24.21.","authors":"Ifechukwuamaka Chinaka, Annabelle Schofield, Christopher I Amos, Lewis R Roberts, Vincent L Chen, Younghun Han, Manal Hassan, Shishir Shetty, Jake P Mann","doi":"10.1016/j.xhgg.2026.100639","DOIUrl":"10.1016/j.xhgg.2026.100639","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish genetic drivers of all-cause HCC across ancestries in a large meta-analysis. We included 15 cohorts comprising 17,697 HCC affected individuals and 2,715,683 control subjects in this meta-analysis. We found 15 genome-wide significant (p < 5 × 10^-8) germline loci, including in/near GCKR, MTTP, ADH5, 8q24.21 (nearest gene MYC), MAP3K9, and GABPB2, and a further two loci found on transcriptome- and regulome-wide association analyses. MAP3K9, TERT, and GABPB2 variants act independently of cirrhosis on both colocalization analysis and sensitivity analyses. There was significant ancestral heterogeneity in six loci including variants in the HLA locus that had divergent effects on HCC risk between East Asian and European ancestries. Fine mapping identified 11 potentially causal coding variants, including p.Leu446Pro (c.1337T>C) in GCKR and p.Asp423Glu (c.1269C>T) in MEN1. MEN1, 8q24.21 (nearest gene MYC), and TERT are all involved in the β-catenin pathway transactivation complex. Transcriptome-wide analysis identified enrichment of germline-encoded DHRS1 in HCC. Regulome-wide analysis replicated the germline signal for EPHA2 and found a chromatin-accessible region containing genes ZNF367 and HABP4. Finally, we demonstrated that population-level genetic architecture for HCC overlaps with steatotic and viral liver disease, and individuals with genetic risk for lower body mass index have higher risk of HCC. Genetic risk for HCC is determined by germline susceptibility to β-catenin pathway activation and cirrhosis. HCC is driven by both heterogeneous and homogeneous genetic factors across ancestries.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100639"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric high-grade gliomas and cancer predisposition syndromes: A retrospective study.","authors":"Selene Cipri, Giada Del Baldo, Emanuele Agolini, Marialetizia Motta, Cecilia Mancini, Claudio Montante, Veronica Capelli, Antonella Cacchione, Mariachiara Lodi, Maria A De Ioris, Sabina Barresi, Isabella Giovannoni, Sabrina Rossi, Evelina Miele, Diana Ferro, Alberto E Tozzi, Angela Gallo, Maria Vinci, Andrea Carai, Rita Alaggio, Antonio Novelli, Marco Tartaglia, Luigi Boccuto, Giovanna Stefania Colafati, Franco Locatelli, Angela Mastronuzzi","doi":"10.1016/j.xhgg.2026.100641","DOIUrl":"10.1016/j.xhgg.2026.100641","url":null,"abstract":"<p><p>The relationship between pediatric and adolescent/young adult (AYA) patients with high-grade gliomas (pediatric high-grade gliomas [pHGGs]) and cancer predisposition syndromes (CPSs) remains insufficiently explored, despite the increasing use of massive parallel sequencing in the diagnostic setting. We retrospectively analyzed sequencing data from 95 pediatric patients diagnosed with HGGs to investigate the presence of germline variants associated with cancer risk. The presence of somatic variants was also evaluated in 15 affected individuals. In silico and in vitro studies were performed to reclassify one variant of uncertain significance (VUS). We identified 80 variants across the 95 patients, including 17 pathogenic (P), 2 likely pathogenic (LP), 60 VUSs, and 1 likely benign (LB), after reclassification. Notably, 23.7% of the P/LP variants were found in genes associated with CPSs. While the distribution of these variants did not show significant differences across tumor subtypes, the highest proportion of P/LP variants was observed in diffuse midline gliomas. Functional studies led to the reclassification of one LZTR1 variant from a VUS to LP. The collected data revealed that 18.9% of patients had P/LP variants; notably, among the 11.6% of patients carrying P/LP variants, there were variants in genes known to be associated with the development of central nervous system (CNS) tumors in pediatric and AYA patients, a rate higher than the 10% incidence typically reported in the literature for pediatric CNS tumors. This finding underscores the value of our comprehensive analysis for germline variants in HGG, suggesting a greater prevalence of CPS in these patients than previously reported.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100641"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic dissection of cardiac iron regulation using transcriptome network analysis and systems genetics in BXD mice.","authors":"Akhilesh K Bajpai, Qingqing Gu, Rakesh Kumar, Xiangtang Li, Athena Starlard-Davenport, Wenjing Zhang, Enkhsaikhan Purevjav, Byron C Jones, Qingyin Zheng, Dong Wang, Lu Lu","doi":"10.1016/j.xhgg.2026.100668","DOIUrl":"10.1016/j.xhgg.2026.100668","url":null,"abstract":"<p><p>Cardiac iron homeostasis is essential for myocardial energy metabolism and contractile function, yet the genetic and molecular mechanisms governing iron levels within the heart remain poorly understood. We used a systems genetics approach to dissect the transcriptional regulation of cardiac iron homeostasis. Myocardial iron level varies substantially across BXD strains (40-112 μg/g) and is under heritable genetic control (H² = 0.38). Elevated cardiac iron is associated with reduced ventricular mass, increased ventricular ectopy, and prolonged atrioventricular conduction in the BXD population. Weighted gene co-expression network analysis of the BXD heart transcriptome identified a co-expression module that was significantly and negatively correlated with cardiac iron levels in both young and old BXD mice and enriched for pathways related to metabolic regulation, cyclic AMP (cAMP) signaling, circadian entrainment, and cardiovascular physiology. The module showed substantial overlap with a curated cardiac iron gene set, and cross-species enrichment analysis confirmed its conservation in human cardiomyopathy differentially expressed genes (enrichment ratio = 1.49; false discovery rate [FDR] = 0.0342). Quantitative trait locus (QTL) mapping of the first principal component of the overlapping module iron genes (n = 38), corroborated by individual gene mapping, identified trans-eQTL hotspots on multiple chromosomes, implicating Fcho2, Gcc2, and Rmdn1 as candidate upstream regulators operating through sequential steps of intracellular iron trafficking. Together, these findings establish a systems-level map of cardiac iron gene regulation, identify candidate genetic regulators, and provide a molecular framework linking disruption of iron-related transcriptional networks to structural and electrical cardiac dysfunction with implications for iron-related heart diseases.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100668"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating shared genetic signals between type 2 diabetes and three neurodegenerative dementia phenotypes.","authors":"Ana Luiza Arruda, Archit Singh, Ozvan Bocher, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini","doi":"10.1016/j.xhgg.2026.100667","DOIUrl":"10.1016/j.xhgg.2026.100667","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) and dementia frequently co-occur, yet the biological mechanisms underlying this comorbidity remain incompletely understood. Here, we systematically investigate shared genetic signals between T2D and three forms of neurodegenerative dementia (Alzheimer disease, Lewy body dementia, and sporadic frontotemporal dementia) using large-scale genome-wide association studies of clinically diagnosed individuals. We identify five genomic regions harboring shared association signals between T2D and at least one dementia subtype. Among these, the APOE locus was common to all dementia subtypes, whereas the remaining four loci (GBA, CRY2/PEX16/MAPK8IP1, INO80E, and NSF) were each shared exclusively between T2D and one dementia subtype. Integrating multi-omics data across several disease-relevant tissues and orthogonal lines of functional evidence, we prioritize 26 candidate genes through which these shared genetic loci potentially mediate their effect. Pathway enrichment highlights lipid and lipoprotein regulatory biology as a central shared axis. Mendelian randomization analyses using genetically regulated gene expression in relevant tissues indicate pleiotropic mechanisms with divergent phenotypic consequences. Our findings identify shared genetic loci between T2D and neurodegenerative dementia, revealing systemic metabolic-neurodegenerative trade-offs and highlighting key genes that underpin the comorbidity, providing a framework for improved understanding of age-related multi-morbidity.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100667"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping long-read sequences to a complete reference genome reveals uncaptured variants across the β-Globin cluster in Africans with sickle cell disease.","authors":"Pamela Lurie, Medhat Mahmoud, Aparna Haldipur, Yixing Han, Qing Li, Edmond Wonkam Tingang, Natalie Asmus, Emilyn Banfield, Nancy J Hall, Bamidele Tayo, Richard Cooper, Titilola Akingbola, George Ayodo, Stephen Obaro, Guillaume Lettre, Qing Meng, Shalini Jhangiani, R Alan Harris, Kim C Worley, Juyhun Kim, Arang Rhie, Adam M Phillippy, Fritz Sedlazeck, Ambroise Wonkam, Neil A Hanchard","doi":"10.1016/j.xhgg.2026.100669","DOIUrl":"10.1016/j.xhgg.2026.100669","url":null,"abstract":"<p><p>African genomes are marked by extensive complexity in the number and distribution of variants yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD)-one of the most common monogenic diseases-has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the β-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes present a challenge to translating these advances to Africa. Here, we align single-molecule long-read sequencing (LRS) targeted to the β-globin region to the human genome build 38 (hg38) and telomere-to-telomere (T2T)-CHM13.v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13.v2 reference sequence at this locus reduces structural variant (SV) calls by 70% and uncovers uncaptured single-nucleotide variants (SNVs). Across the cluster, we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed, we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4 kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100669"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clustered monoallelic mosaicism in twins suggests previously unrecognized path of mutagenesis.","authors":"Jonas Böhnlein, Johann G Maass, Julia Dennig, Sebastian Burkart, Lilian T Kaufmann, Michelle Brehm, Kirsten Göbel, Annette Kopp-Schneider, Tim Holland-Letz, Laurine K Sprehe, Katrin Hinderhofer, Maja Hempel, Christian P Schaaf","doi":"10.1016/j.xhgg.2026.100636","DOIUrl":"10.1016/j.xhgg.2026.100636","url":null,"abstract":"<p><p>We report monozygotic twins with HNRNPU-related neurodevelopmental disorder who harbor two closely spaced mosaic single-nucleotide deletions on the same allele (c.1463del [p.Pro488Glnfs∗13] and c.1466del [p.Lys489Argfs∗12]). The variants are mutually exclusive on individual DNA molecules and result in three distinct cellular lineages within each individual. We term this rare genotypic configuration clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore potential mechanisms for its origin. Based on our analysis, we propose that this genotype arises from a single mutational event in an early embryonic cell, yielding divergent outcomes on sister chromatids. Screening of large datasets (COSMIC and MosaicBase) identified additional cMoMa-like cases, suggesting that the mechanism is not unique to our case but may represent a broader, previously unrecognized path of mutagenesis that extends our current definition of mosaicism.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100636"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}